IL-10 release requires stronger toll-like receptor 4-triggering than TNF: a possible explanation for the selective effects of heterozygous TLR4 polymorphism Asp(299)Gly on IL-10 release.
The toll-like receptor 4 Asp(299)Gly polymorphism results in an inactive receptor. Heterozygosis is associated with reduced LPS-inducible IL-10 protein and IL-10 mRNA from blood leukocytes and isolated monocytes, while numerous other mediators are not affected. We could exclude that this effect is due to the differences in the kinetics of IL-10 release, in the expression of total surface TLR4 or in LPS-binding to monocytes between subjects heterozygous for the Asp(299)Gly polymorphism or homozygous carriers of the wild-type allele. Furthermore, we could show that IL-10 induction in general requires stronger LPS-triggering than TNF and is more sensitive to LPS inhibitors. The lower number of responsive wild-type TLR4 receptors on monocytes of heterozygotes may explain why only IL-10 release is affected.
Dehus
Oliver
O
Biochemical Pharmacology, University of Konstanz, P.O.Box M668, 78457 Konstanz, Germany.
Bunk
Sebastian
S
von Aulock
Sonja
S
Hermann
Corinna
C
D000483:Alleles; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007113:Immunity, Innate; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*
D008070:Lipopolysaccharides; D012333:RNA, Messenger; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10